Metabolic Signalling in Muscle- and Adipose-tissue Following Insulin Withdrawal and Growth Hormone Injection.
Information source: University of Aarhus
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Diabetes Mellitus Type I; Ketoacidosis
Intervention: Insulin withdrawal (Drug); Norditropin (Drug)
Phase: N/A
Status: Recruiting
Sponsored by: University of Aarhus Official(s) and/or principal investigator(s): Niels Møller, MD, Study Chair, Affiliation: Aarhus University / Aarhus University Hospital Thomas Voss, MD, Principal Investigator, Affiliation: Aarhus University / Aarhus University Hospital
Overall contact: Thomas Voss, MD, Phone: +45 29911146, Email: tsvo@ki.au.dk
Summary
Diabetes mellitus type I (DM I) is characterized by lack of endogenous insulin and these
patients are 100% dependent on insulin substitution to survive.
Insulin is a potent anabolic hormone with its primary targets in the liver, the skeletal
muscle-tissue and - adipose-tissue.
Severe lack of insulin leads to elevated blood glucose levels, dehydration, electrolyte
derangement, ketosis and thus eventually ketoacidosis.
Insulin signalling pathways are well-known.
Growth hormone (GH) is also a potent anabolic hormone, responsible for human growth and
preservation of protein during fasting. GH (in concert with lack of insulin) induces
lipolysis during fasting. It is not known how GH exerts its lipolytic actions.
The aim is to define insulin and growth hormone (GH) signalling pathways in 3 different
states in patients with DM I.
And to test whether ATGL-related lipolysis in adipose tissue contributes to the development
of ketosis.
1. Good glycemic control
2. Lack of insulin (ketosis/ketoacidosis)
3. Good glycemic control and GH injection
Clinical Details
Official title: Metabolic Signalling in Muscle- and Adipose Tissue Following Insulin Withdrawal and Growth Hormone Injection in Type I Diabetes Mellitus, a Clinical Experimental Study.
Study design: Allocation: Randomized, Intervention Model: Factorial Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science
Primary outcome: Insulin and growth hormone signalling, expressed as CHANGE in phosphorylation of intracellular target proteins and CHANGE in mRNA expression of target genes in muscle- and fat-tissue.
Secondary outcome: Change in Intracellular markers of lipid metabolism in muscle- and fat tissue biopsies.Metabolism Ghrelin
Detailed description:
Diabetes mellitus type I (DMI ) is characterized by lack of endogenous insulin and these
patients are 100% dependent on insulin substitution to survive.
Insulin is a potent anabolic hormone with its primary targets in- the liver, - the skeletal
muscle-tissue and - fat-tissue.
In the liver it enhances glycogenesis and inhibits glycogenolysis and gluconeogenesis.
In skeletal muscle-tissue, it enhances glucose transport into the cell, glycogenesis,
glycolysis, glucose oxidation and protein synthesis.
In fat-tissue, it inhibits lipolysis and enhances lipogenesis.
This indicates that a fall in serum insulin levels lead to increased blood glucose and
increased levels of FFA's (free fatty acids) in the blood - eventually leading to ketone
production.
If this condition is not corrected, it will lead to ketoacidosis, which is a potentially
life-threatening condition, that is to be corrected under hospital admission with
fluid-therapy, electrolyte- and insulin-substitution.
Insulin has been studied thoroughly and signalling pathways are well known.
An interesting pathway is suppression of lipolysis. The most important and rate-limiting
lipase in triglyceride hydrolysis is adipose triglyceride lipase (ATGL)(1-5). A connection
between ATGL and G0/G1 switch gene (G0S2) has been shown (6,7). During lipolysis ATGL is
up-regulated and G0S2 is down-regulated and the promoter region for G0S2 has binding-sites
for glucose, insulin dependent transcription factors and peroxisome proliferator-activated
receptors y (PPAR-y)(8).
One former study has shown that fasting reduces G0S2 and increases ATGL in humane
adipose-tissue(7).
The anti-lipolytic effects of insulin, could be thought, to be mediated through increased
transcription of G0S2 which then in turn inhibits ATGL. Conversely, increased lipolysis
during lack of insulin.
Growth hormone and growth hormone dependent synthesis og IGF-1 (Insulin-like growth factor -
1) is crucial for human growth before and during adolescence. As an adult GH and IGF-1 are
still potent growth factors and also they exert essential regulatory properties on human
metabolism(9,10)
GH- signalling pathways go through the GH-receptor, which phosphorylates and thus activates
the receptor associated Janus Kinase 2 (JAK2). The signals from this point have been
examined in numerous studies.
In rodents, the signal has been shown to run three ways (9,10) Studies on human fibroblast
cells have been able to support two of these pathways (MAPK - mitogen-activated protein
kinase and STAT - signal transducer and activator of transcription), but not through the
insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3-K) pathway.
In human (in vivo) studies, GH stimulation and phosphorylation of STAT5 has been evident,
however an association between GH stimulation and activation of MAPK and PI3-K has not been
shown (11).
The latter is interesting and remarkable, considering the insulin-agonistic and antagonistic
effects of GH.
GH stimulates lipolysis, but exactly how the lipolytic properties of GH are mediated is not
fully understood. However, it is shown that GH has an effect on hormone-sensitive lipase
(12) (HSL).
Other options could be, as found in rodents, interaction via PI3-K signaling pathway or via
G0S2/ATGL interaction, either directly or perhaps mediated through IGF-1.
Humane intracellular signaling-pathways during development of ketosis/ketoacidosis are not
well-known. The investigators believe that understanding these pathways and the exact
mechanisms behind the development of ketoacidosis, is of great importance.
Eligibility
Minimum age: 18 Years.
Maximum age: 65 Years.
Gender(s): Male.
Criteria:
Inclusion Criteria:
Diagnosis of Diabetes Mellitus Type I, C-peptide negative, 19 < BMI < 26, Written consent
-
Exclusion Criteria:
Ischemic heart disease, Cardiac arrythmia, Epilepsy, Other medical illness
-
Locations and Contacts
Thomas Voss, MD, Phone: +45 29911146, Email: tsvo@ki.au.dk
Institute of Clinical Medicine, Aarhus, Aarhus C 8000, Denmark; Recruiting Thomas Voss, MD, Phone: +45 29911146, Email: tsvo@ki.au.dk Niels Møller, MD, Phone: +45 78462165, Email: nielsem@dadlnet.dk Thomas Voss, MD, Principal Investigator
Additional Information
Related publications: Bezaire V, Mairal A, Ribet C, Lefort C, Girousse A, Jocken J, Laurencikiene J, Anesia R, Rodriguez AM, Ryden M, Stenson BM, Dani C, Ailhaud G, Arner P, Langin D. Contribution of adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in hMADS adipocytes. J Biol Chem. 2009 Jul 3;284(27):18282-91. doi: 10.1074/jbc.M109.008631. Epub 2009 May 11. Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006 May 5;312(5774):734-7. Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Rydén M, Arner E, Sicard A, Jenkins CM, Viguerie N, van Harmelen V, Gross RW, Holm C, Arner P. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005 Nov;54(11):3190-7. Schweiger M, Schreiber R, Haemmerle G, Lass A, Fledelius C, Jacobsen P, Tornqvist H, Zechner R, Zimmermann R. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem. 2006 Dec 29;281(52):40236-41. Epub 2006 Oct 30. Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004 Nov 19;306(5700):1383-6. Yang X, Lu X, Lombès M, Rha GB, Chi YI, Guerin TM, Smart EJ, Liu J. The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 2010 Mar 3;11(3):194-205. doi: 10.1016/j.cmet.2010.02.003. Nielsen TS, Vendelbo MH, Jessen N, Pedersen SB, Jørgensen JO, Lund S, Møller N. Fasting, but not exercise, increases adipose triglyceride lipase (ATGL) protein and reduces G(0)/G(1) switch gene 2 (G0S2) protein and mRNA content in human adipose tissue. J Clin Endocrinol Metab. 2011 Aug;96(8):E1293-7. doi: 10.1210/jc.2011-0149. Epub 2011 May 25. Teunissen BE, Smeets PJ, Willemsen PH, De Windt LJ, Van der Vusse GJ, Van Bilsen M. Activation of PPARdelta inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts. Cardiovasc Res. 2007 Aug 1;75(3):519-29. Epub 2007 May 3. Birzniece V, Sata A, Ho KK. Growth hormone receptor modulators. Rev Endocr Metab Disord. 2009 Jun;10(2):145-56. doi: 10.1007/s11154-008-9089-x. Review. Møller N, Jørgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24. Review. Silva CM, Kloth MT, Whatmore AJ, Freeth JS, Anderson N, Laughlin KK, Huynh T, Woodall AJ, Clayton PE. GH and epidermal growth factor signaling in normal and Laron syndrome fibroblasts. Endocrinology. 2002 Jul;143(7):2610-7. Beauville M, Harant I, Crampes F, Riviere D, Tauber MT, Tauber JP, Garrigues M. Effect of long-term rhGH administration in GH-deficient adults on fat cell epinephrine response. Am J Physiol. 1992 Sep;263(3 Pt 1):E467-72.
Starting date: May 2014
Last updated: October 15, 2014
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